Carin Wittnich

Gender-Differences in Myocardial Adaptation to Afterload in Normotensive and Hypertensive Rats

Echocardiographic studies suggest that women appear to exhibit a greater degree of myocardial hypertrophy in response to increased afterload than men. Therefore, gender differences and the role of estrogen and testosterone in the development of myocardial hypertrophy were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Male and female rats were either surgically neutered or underwent a sham operation at 21 days of age. A subgroup of neutered females of each strain received 17&bgr;-estradiol replacement. At 6 months, the heart weight–to–body weight ratio was assessed and correlated with systemic blood pressure. Compared with males, females had significantly smaller body and heart weights in both normotensive and hypertensive strains. Despite this, females consistently had significantly greater heart weight–to–body weight ratios. In females, neutering significantly lowered the heart weight–to–body weight ratio in WKY rats, which was returned to intact levels with estrogen replacement. Female SHR showed similar, but not statistically significant, responses. In males, neutering appeared to result in a higher heart weight–to–body weight ratio in WKY rats, but the opposite was seen in SHR. In addition, there was a significant correlation between arterial blood pressure and heart weight–to–body weight ratio (systolic r =0.45, P =0.0015: diastolic r =0.52, P =0.0002) in intact males and females of both strains, and for a given diastolic pressure, females always exhibited a greater heart weight–to–body weight ratio than males. Thus, a greater degree of myocardial hypertrophy in females appears to be related to the presence of estrogen in both normotensive and hypertensive rats. Females show a stronger relationship between heart/body weight and blood pressure than males, which occurred independent of the presence of estrogen.

Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease

OBJECTIVE The outcome of children with cyanosis after cardiac surgical procedures is inferior to that of children who are acyanotic. Animal studies indicated detrimental effects of chronic hypoxia on myocardial metabolism and function. We studied whether the presence or the degree of cyanosis adversely affected myocardial adenosine triphosphate, ventricular function, and clinical outcome in children. METHODS Forty-eight children who underwent repair of tetralogy of Fallot were divided according to their preoperative saturation: group I, 90% to 100% (n = 14 patients); group II, 80% to 89% (n = 16 patients); and group III, 65% to 79% (n = 18 patients). Adenosine triphosphate was measured from right ventricular biopsy specimens taken before ischemia, at 15 minutes of ischemia, at end-ischemia, and at 15 minutes of reperfusion. Ejection fraction was measured by echocardiography. RESULTS Even before surgical ischemia, compared with groups I and II, group III had lower preoperative ejection fraction (59% +/- 2.9% vs 67% +/- 1.7% and 68% +/- 1.0%; P <.01) and lower preischemic adenosine triphosphate levels (15.1 +/- 2.1 vs 19.1 +/- 1.9 and 21.4 +/- 1.5 micromol/g dry weight; P <.01). After 15 minutes of ischemia, group III had lower adenosine triphosphate levels (11.2 +/- 1.8 vs 14.77 +/- 2.3 and 17. 6 +/- 3.1 micromol/g dry weight; P <.01). With reperfusion, both cyanotic groups lost further adenosine triphosphate compared with partial recovery in the acyanotic group (-22% +/- 3.8%, -20% +/- 3. 1% vs +18% +/- 1.8%; P <.01). Children in group III had a more complicated postoperative course as evidenced by longer ventilatory support (85 +/- 25 hours vs 31 +/- 15 and 40 +/- 21 hours; P =.07), inotropic support (86 +/- 23 hours vs 38 +/- 12 and 36 +/- 4 hours; P <.01), and intensive care unit stay (160 +/- 35 hours vs 60 +/- 10 and 82 +/- 18 hours; P =.02). CONCLUSIONS The degree of cyanosis adversely affects myocardial adenosine triphosphate, function, and clinical outcome of children who undergo cardiac operation. Children with cyanosis should be identified as a higher risk group that could be targeted for supportive interventions.

Sex differences in myocardial metabolism and cardiac function: an emerging concept

There is substantial evidence that there are dramatic sex-related differences in the incidence of cardiovascular disease, apparently related to the presence of steroid hormones. This is supported by the discovery of steroid hormone receptors in the heart and vasculature. More controversial is the area of sex-related differences in cardiac metabolism and function. A number of human and animal studies have demonstrated that estrogen and testosterone have cardiac metabolic effects. Additionally, research shows females have higher heart rates and various indices of function, including cardiac output and stroke volume, compared with males. However, some controversy exists, as other studies report that function in isolated muscle preparations is lower in females versus males. The reasons for these differences may reflect effects of sex hormones that are dependent on the conditions being studied. Cardiac function is reduced in postmenopausal females, suggesting that female sex hormones, specifically estrogen and progesterone, influence cardiac function. Apart from its well-documented vasodilatory effects, estrogen has also been shown to have negative inotropic effects and to reduce Ca2+ transients in cardiomyocytes. Similar results have been found for progesterone. Several studies show that testosterone administration appears to increase cardiac performance, while others show that it increases the stiffness of the ventricle due to increased collagen synthesis, thereby reducing diastolic performance. This review will discuss current evidence suggesting sex-related differences in cardiac metabolism and its energetics and function and will present the potential role of the principal sex steroid hormones.

Does hyperoxia affect glucose regulation and transport in the newborn

OBJECTIVE Hyperglycemia has been found to occur in children placed on cardiopulmonary bypass. Our laboratory demonstrated that hyperoxia plays a role in this hyperglycemic response and also occurs in the absence of cardiopulmonary bypass. The purpose of this study was to elucidate potential mechanisms underlying the hyperoxic-induced hyperglycemia by examining glucagon, insulin, and epinephrine, which are important in glucose regulation and skeletal and cardiac glucose transporters (GLUT1 and GLUT4), which facilitate glucose entry. METHODS Three-day-old piglets were anesthetized, intubated, and ventilated to normoxia. Animals were then randomly allocated to either 5 hours of normoxia (n = 4) or hyperoxia (n = 6). Measurements of oxygen, blood glucose, plasma glucagon, insulin, and epinephrine levels were made. Total GLUT1 and GLUT4 content in cardiac and skeletal muscle was measured using Western blotting analysis. RESULTS A sustained hyperglycemic response (P <.001) was seen throughout the 5-hour ventilatory period. A significant twofold elevation in glucagon levels (P <.001) and a threefold elevation (P <.003) in plasma insulin levels occurred, despite no significant changes in plasma epinephrine. Total GLUT1 and GLUT4 content were significantly reduced in skeletal muscle by 66% and 59%, respectively, while no significant changes occurred in cardiac muscle. CONCLUSION This study demonstrates that significant elevations in glucagon and insulin and reductions in total skeletal muscle GLUT1 and GLUT4 content all contribute to hyperoxia-induced hyperglycemia seen in newborns. To optimize postoperative recovery of newborns, consideration should be given to the levels of oxygen used to avoid the potential development of insulin resistance and subsequent decrease in glucose entry.

Operation for acute postinfarction mitral insufficiency using continuous oxygenated blood cardioplegia

Patients with acute-onset mitral insufficiency and cardiogenic shock after myocardial infarction have a high incidence of operative death and morbidity. Patients with ventricular dysfunction, myocardial ischemia, and limited cardiac reserve undergoing an urgent operation represent a challenge to modern methods of myocardial protection. To improve results of operation a new technique was devised with continuous infusion of cold oxygenated blood cardioplegia during the entire cross-clamp period. Between 1984 and 1988, 19 consecutive patients with severe mitral regurgitation and cardiogenic shock (systolic blood pressure less than 60 mm Hg) after myocardial infarction underwent urgent myocardial revascularization, mitral valve replacement, or both. Left ventricular ejection fraction was less than 40% in 16 of 19 patients. All patients had suffered myocardial infarction within 4 weeks of operation and underwent an urgent operation within 24 hours of the onset of hemodynamic compromise. Severe three-vessel coronary artery disease was present in 16 of the 19 patients. A continuous infusion of blood cardioplegia was instituted at aortic cross-clamping and continued throughout the cross-clamp period. Infusion of continuous blood cardioplegia was also instituted through each completed distal vein graft. Myocardial septal and left ventricular apical temperatures were maintained at 10 degrees +/- 2 degrees C throughout the cross-clamp period. There were two in-hospital deaths (mortality, 10.5%) and low output syndrome was present in 10 patients (53%). At a mean follow-up of 2.5 years, there was one late death and 14 of the 16 remaining patients were in New York Heart Association functional class I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hyperoxia on neonatal myocardial energy status and response to global ischemia

BACKGROUND This study examines the effect of neonatal exposure to clinically relevant hyperoxia levels on both in vivo myocardial metabolism and the subsequent metabolic response to global ischemia. METHODS Three-day-old pigs were ventilated to normoxia (80 mm Hg, 2 or 5 hours, n = 11), mild hyperoxia (250 mm Hg, 2 hours, n = 9), or severe hyperoxia (500 mm Hg, 5 hours, n = 14). Ventricular biopsies obtained at the end of the ventilation period, and at early and late ischemia were analyzed for ATP, ADP, AMP, creatine phosphate, glycogen, and lactate. RESULTS Hyperoxia did not significantly alter in vivo metabolism. During early ischemia, hearts exposed to severe hyperoxia had better ATP and glycogen preservation (p < 0.003). These hearts exhibited almost complete (92%) creatine phosphate depletion, in contrast to incomplete creatine phosphate use in all other neonatal hearts, even in the face of 30% ATP reductions. However, hearts exposed to severe hyperoxia also had a higher incidence of fibrillation during ischemia, which accelerated ATP and glycogen degradation. CONCLUSIONS Although severe hyperoxia provided an energy-sparing effect during early ischemia, it also increased the incidence of ventricular fibrillation, which negated this beneficial effect.

Ventricle-Specific Metabolic Differences in the Newborn Piglet Myocardium In Vivo and During Arrested Global Ischemia

Ventricular dysfunction is reported greater in the left (LV) versus right ventricle (RV) in infants following surgically induced ischemia. Ventricle-specific differences in baseline metabolism may alter response to ischemia thus affecting postischemic functional recovery. This study identifies ventricle-specific metabolic differences in the newborn (piglet) heart at baseline (working) and during ischemia (arrested). Baseline LV citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HAD) activities were 15% and 18% lower (p < 0.02), whereas creatine kinase (CK) and phosphofructokinase (PFK) activities were 40% and 23% higher (p < 0.04) than the RV. Baseline LV glycogen reserves were also 55% higher (p = 0.004). By 15 min of ischemia, LV ATP was 20% lower (p < 0.05), lactate was 51% higher (p = 0.001), and hydrogen ions (H+) were 43% higher (p = 0.03) compared with the RV. These differences persisted for the entire ischemic period (p < 0.02). After 45 min of ischemia, the LV used 58% less (p < 0.05) glycogen than the RV. These findings demonstrate that the enhanced glycolytic capacity of the newborn LV was accompanied by greater anaerobic end-product accumulation and lower energy levels during ischemia. This profile may offer one explanation for greater LV-dysfunction relative to the RV in children following ischemia.

Impact of female sex hormones on liver tissue lactic acidosis during ischemia.

Background. Lower liver transplant success is observed when the donor is female. Intracellular acidosis during ischemia is proposed to contribute to the injury sustained by the transplanted organ and its role in livers obtained from nonheartbeating donors is unclear. Research has shown that livers of female rats develop a greater degree of intracellular acidosis during ischemia than males. This work explores the role of sex hormones in mediating this sex difference. Methods. Subgroups of neutered female rats were given 17 β-estradiol (E), progesterone (P), or combination (E+P). To compare the effects of female sex hormones in males, subgroups of intact and castrated males received 17 β-estradiol. In vivo and ischemic liver biopsies were taken and analyzed for lactate and H+. Results. Although there was no effect of hormone therapy on baseline metabolic parameters, during ischemia compared to neutered females, livers from E females significantly (P<0.01) increased lactate by 56% and H+ by 71%, while E+P significantly increased only lactate (39%; P<0.05). Livers from neutered males given 17 β-estradiol showed significantly greater (P<0.001) accumulation of lactate (80%) and H+ (79%). This was even shown in intact males, where despite a blunted response, 17 β-estradiol, significantly (P<0.05) increased lactate by 39% and H+ by 25%. Conclusion. This study illustrates the mechanisms for the sex difference in the liver’s metabolic response to ischemia are estrogen mediated, which is seen even in the presence of male hormones, thus offering one explanation for the lower liver transplant success when the donor is female.

Metabolic and Functional Response of Neonatal Pig Hearts to the Development of Ischemic Contracture: Is Recovery Possible?

The potential for functional and metabolic recovery in neonatal hearts after the development of ischemic contracture remains controversial and undefined. This study documents postischemic recovery of metabolism and function in the in vivo neonatal heart after the development of onset and peak ischemic contracture. In piglets on cardiopulmonary bypass, hearts were reperfused after the development of either onset (TICo) or peak (TICp) ischemic contracture. Systolic (developed and systolic function, contractility) and diastolic (diastolic function, relaxation) performance was assessed throughout reperfusion. Biopsies were obtained at end-ischemia or end-reperfusion to assess metabolism. By end-ischemia, the metabolic profiles of both TICo and TICp hearts confirmed energy-store depletion and purine degradation that was quantitatively greater in TICp hearts. Hearts reperfused at TICo had consistent moderate impairment of developed function, contractility, diastolic function, and relaxation, whereas hearts reperfused at TICp had much more profound functional impairment. Diastolic function showed the worst functional recovery. In contrast, systolic function was not significantly altered in either study group and, thus, did not reflect the actual extent of injury. In addition, TICo hearts either did not further deplete or partially regenerated energy stores during reperfusion, whereas TICp hearts had further energy-store depletion and lactate accumulation. In summary, neonatal hearts reperfused after TICo maintained or partially restored energy stores and had significant but incomplete functional recovery. In contrast, further metabolic deterioration and profound functional impairment occurred with reperfusion after TICp, potentially indicating ongoing mitochondrial injury and compromised oxidative phosphorylation.

A method for decontamination of animals involved in floodwater disasters

A method for decontamination of animals involved in floodwater disasters